leptin and Renal-Insufficiency

Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Heart; Heart Failure; Humans; Hypoglycemic Agents; Intra-Abdominal Fat; Kidney Tubules; Leptin; Models, Biological; Myocardium; Obesity; Renal Insufficiency; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume

Effects of online hemodiafiltration (HDF) using acetate-free bicarbonate dialysis (AFD) fluid on microinflammation, resulting in improved nutritional status in hemodialysis patients, were examined and compared with conventional acetate-containing bicarbonate dialysis (ACD) fluid. A total of 24 hemodialysis patients were registered for a cross-over design study for a 6-month period. These patients were subjected to ACD for the first 3 months followed by AFD fluid for the latter 3 months. Blood variables of C-reactive protein (CRP), interleukin-6 (IL-6), leptin, neuropeptide Y (NPY), protein catabolic rate (PCR) and %creatinine (Cr) index were determined after the first and last 3-month period. The filters and the conditions of HDF and drug regimens including erythropoiesis-stimulating agents were unchanged throughout the cross-over study. Predialysis blood pH and bicarbonate were significantly higher in the AFD phase than in the ACD phase. Blood CRP and IL-6 levels were significantly decreased in the AFD group compared to the ACD group. Concerning nutritional evaluation, leptin and NPY were significantly lower and higher, respectively, in the AFD phase than in the ACD phase. PCR tended to be higher in the AFD phase than in the ACD phase. A significantly higher %Cr index level was observed in the AFD phase than in the ACD phase. These results suggest that online HDF using AFD fluid contributes to alleviating bioincompatible events associated with microinflammation, leading to improvement in the nutritional status in hemodialysis patients.

Topics: Acetates; Adult; Aged; C-Reactive Protein; Cross-Over Studies; Female; Hemodiafiltration; Humans; Inflammation; Interleukin-6; Leptin; Male; Middle Aged; Neuropeptide Y; Nutritional Status; Renal Dialysis; Renal Insufficiency; Treatment Outcome

To assess whether endocrine dysfunction may cause derangement in energy homeostasis in patients undergoing hemodialysis (HD), we profiled hormones, during a 3-day period, from the adipose tissue and the gut and the nervous system around the circadian clock in 10 otherwise healthy HD patients and 8 normal controls. The protocol included a 40-h fast. We also measured energy-protein intake and output and assessed appetite and body composition. We found many hormonal abnormalities in HD patients: 1) leptin levels were elevated, due, in part, to increased production, and nocturnal surge in response to daytime feeding, exaggerated. 2) Peptide YY (PYY), an anorexigenic gut hormone, was markedly elevated and displayed an augmented response to feeding. 3) Acylated ghrelin, an orexigenic gut hormone, was lower and did not exhibit the premeal spike as observed in the controls. 4) neuropeptide Y (NPY), a potent orexigenic peptide, was markedly elevated and did not display any circadian variation. 5) Norepinephrine, marginally elevated, did not exhibit the normal nocturnal dip. By contrast, α-melanocyte-stimulating hormone and glucagon-like peptide-1 were not different between the two groups. Despite these hormonal abnormalities, HD patients maintained a good appetite and had normal body lean and fat mass, and there was no evidence of increased energy expenditure or protein catabolism. We explain the hormonal abnormalities as well as the absence of anorexia on suppression of parasympathetic activity (vagus nerve dysfunction), a phenomenon well documented in dialysis patients. Unexpectedly, we noted that the combination of high leptin, PYY, and NPY with suppressed ghrelin may increase arterial blood pressure, impair vasodilatation, and induce cardiac hypertrophy, and thus could predispose to adverse cardiovascular events that are the major causes of morbidity and mortality in the HD population. This is the first report attempting to link hormonal abnormalities associated with energy homeostasis to adverse cardiovascular outcome in the HD patients.

Topics: Adult; Anorexia; Appetite; Body Composition; Cardiovascular Diseases; Circadian Rhythm; Endocrine System Diseases; Energy Metabolism; Fasting; Female; Ghrelin; Homeostasis; Humans; Leptin; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Peptide YY; Protein-Energy Malnutrition; Renal Dialysis; Renal Insufficiency; Risk Factors

Extreme replacement of skeletal muscles by adipose tissue was found in an 86-year old Japanese male cadaver during dissection practice for medical students at Oita University School of Medicine. Especially, the bilateral sartorius muscles looked overall like adipose tissue. The man had suffered from diabetes mellitus, renal failure, hypertension and hypothyroidism before his death. He was also an alcohol drinker. He had been bedridden late in life. The cause of death was renal failure. In microscopy, the adipose tissue-like sartorius muscle was shown to consist of leptin-positive adipocytes with a small number of degenerated muscle fibers. Fatty replacement, or fatty degeneration, appears to result from endocrine and metabolic disorders, and being bedridden leads to muscle atrophy and damage, although the origin of the adipocytes which emerged in the degenerated muscles is unknown.

Topics: Adipocytes, White; Adipose Tissue, White; Aged, 80 and over; Body Fat Distribution; Cadaver; Comorbidity; Diabetes Mellitus; Humans; Hypertension; Hypothyroidism; Leptin; Male; Muscle, Skeletal; Renal Insufficiency

Possible correlations between adiponectin, leptin, CD146, a novel adhesion molecule localized at the endothelial junction, and other markers of endothelial cell injury, von Willebrand factor, thrombomodulin, vascular cell adhesion molecule, and intracellular adhesion molecule, and markers of inflammation, tumor necrosis factor-alpha, interleukin-6, and high-sensitivity C-reactive protein in nondiabetic hemodialyzed patients with and without coronary artery disease were studied. Markers of endothelial dysfunction were elevated in hemodialyzed patients, predominantly with coronary artery disease. In multivariate analysis, kinetic urea modeling and plasminogen activator inhibitor-1 remained the only positive predictors of adiponectin. In multivariate analysis, predictors of leptin were triglycerides, tissue plasminogen activator, CD146, and coronary artery disease. In multivariate analysis, predictors of CD146 were age, hemoglobin, and adiponectin. Elevated adiponectin correlated to CD146 may be the expression of a counterregulatory response aimed at mitigating the consequences in endothelial damage and increased cardiovascular risk in renal failure. The data provide further support for a link between adipocytokines, endothelial dysfunction, cardiovascular risk, and renal failure.

Topics: Adipocytes; Adipokines; Adiponectin; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Case-Control Studies; CD146 Antigen; Endothelium, Vascular; Female; Humans; Leptin; Male; Middle Aged; Renal Dialysis; Renal Insufficiency; Risk Factors

Noninfectious complications of peritoneal dialysis (PD) are increasing in relative importance due to success in decreasing the rate of PD peritonitis. Mechanical catheter complications are emerging as an important cause of technique failure at the same time as experience with PD is declining in North America. There is also increasing interest in metabolic complications of PD and in glucose-sparing strategies to reduce the risk for hyperglycemia, hyperinsulinemia, and hyperleptinemia. This clinical commentary focuses on these noninfectious complications of PD.

Topics: Glucose; Humans; Hyperglycemia; Hyperinsulinism; Leptin; Peritoneal Dialysis; Peritonitis; Renal Dialysis; Renal Insufficiency

Leptin is a protein produced by fat cells and involved in body weight regulation. In patients with normal kidney function, leptin has been considered an independent predictor of cardiovascular events. In uremic patients, leptin in plasma serum was assumed to be associated with malnutrition, inflammation and atherosclerosis. Because of its molecular weight and characteristics, leptin can be considered as a protein-bound uremic retention solute. Some authors have reported the possibility of decreasing the serum leptin concentration with high flux membranes, but limited data are available on the elimination with medium-flux membranes or alternative dialysis strategies such as hemodiafiltration.. We evaluated the kinetics of leptin and beta2m in a study of 18 chronic hemodialysis patients using low-flux, medium-flux and high-flux biocompatible membranes, the last one used in hemodiafiltration (HDF). Blood samples for leptin and beta2m were collected pre- and post-treatment and 30 minutes after the end of treatment, over a 1-week period that included 3 dialysis sessions. Clearances of leptin and beta2m across the dialyzer were also determined directly from the arterial and venous blood concentrations 60 and 210 minutes after starting dialysis.. At baseline, all groups showed similar leptin (18.8+/-4.4 ng/mL) and beta2m concentrations (29.2+/-7.1 ng/mL). After a single dialysis session, a reduction of both solutes was observed with HDF (39.8+/-1.9%, 78.1+/-4.9) and medium flux membranes (18.2+/-0.9%, 52.2+/-1.7%), whereas the concentrations remained unchanged with the low-flux membranes. After one-week period, a trend of reduction of plasma pre dialysis leptin and beta2m were observed with HDF and medium flux membranes. At 60 minutes, HDF showed the best instantaneous clearance across the filter for leptin (56.2+/-10.1 ml/min) and beta2m (75.3+/-4.4 ml/min). The magnitude of post dialysis rebound of leptin at 30 min was variable and strongly correlated with the instantaneous clearance of the solute (r2= 0.88).. Leptin serum concentration can be influenced by dialysis modalities and membrane permeability; data on rebound suggest a multicompartimental kinetic of leptin similar to beta2m. Leptin removal, as measured by the reduction rate, can be considered as an index of dialysis efficiency for protein-bound uremic retention solutes.

Topics: Aged; beta 2-Microglobulin; Female; Humans; Leptin; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

Chronic inflammation is prevalent in dialysis patients. We investigated the relationship between inflammation and newly identified adipokines: leptin and adiponectin in this population. A total of 129 chronic hemodialysis patients were collected. Serum high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), leptin and adiponectin levels were determined as well as other metabolic variables. Correlation studies and multiple regression analysis were performed among variables. Our results showed that hemodialysis patients had elevated levels of inflammatory markers, leptin and adiponectin. Diabetic subjects had higher serum CRP and lower albumin levels than non-diabetics. Serum CRP levels were positively correlated with IL-6 levels and negatively correlated with albumin levels. Serum leptin levels were directly related to CRP levels while adiponectin levels were inversely related to CRP levels. A significant negative correlation was observed between serum leptin and adiponectin levels. Serum IL-6 levels were the single independent factor affecting CRP levels. Body mass index can predict both serum leptin and adiponectin levels. We conclude that hemodialysis patients are at an increased risk of chronic inflammation and diabetes patients are even more susceptible to this status. Both serum leptin and adiponectin levels are associated with inflammatory markers. As adipose tissue is the major secreting site of these adipokines, our results suggest that adipose tissue plays an important role in the pathogenesis of chronic inflammation in dialysis patients.

Topics: Adiponectin; Age Factors; Biomarkers; Body Mass Index; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Male; Middle Aged; Regression Analysis; Renal Dialysis; Renal Insufficiency; Serum Albumin; Sex Factors